Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) are a cause of premature deaths, responsible for up to 8% of sudden deaths in industrialized countries. Identifying individuals at risk for TAAD allows for medical management that prevents deaths due to dissections. We determined that up to 20% of TAAD patients without a known genetic syndrome have a family history of TAAD, which is inherited primarily in an autosomal dominant manner (termed heritable thoracic aortic disease, HTAD). We established a cohort of HTAD families (842 families with two or more members with TAAD) and used this cohort to identify novel HTAD genes. Positional cloning and candidate gene approaches by our lab and others have successfully identified 18 genes for HTAD. We hypothesize that there are multiple altered genes yet to be identified, disrupting known and novel molecular pathways responsible for thoracic aortic disease, and responsible for disease in the unsolved HTAD families. The overarching goal of the project is to identify the remaining genes for HTAD, characterize the phenotype associated with these novel genes, perform initial molecular studies linking the mutant gene to aortic disease, and rapidly translate these findings into improved clinical care and prevention of premature deaths due to aortic dissection in HTAD families. The proposed aims are: (1) Recruit and characterize additional HTAD families to be used to identify novel genes, and delineate the clinical features and mutation spectrum associated with new genes; (2) Pursue exome/genome sequencing on HTAD cases and use the genetic strategies to identify novel genes, including segregation of rare variants in affected relatives and trios (affected proband and unaffected parents) and burden analyses; (3) Pursue a machine-learning approach using exome data from HTAD families and controls to identify novel disease genes; (4) Perform initial molecular and cellular biology studies of novel HTAD genes to confirm a link between the mutant gene and thoracic aortic disease. In summary, we are uniquely poised to identify novel HTAD genes using our assembled cohort and are proposing both proven and novel strategies to identify additional HTAD genes. Uncovering HTAD genes is crucial for identifying individuals at risk for aortic dissections and initiating gene-specific clinical management to prevent premature death due to dissections.